Synthesis and evaluation of trimetoquinol derivatives: Novel thromboxane A2/prostaglandin H2 antagonists with diminished β-adrenergic agonist activity

Article abstract of DOI:10.1021/jm950896w

Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at β-adrenergic (S >> R) and antagonism at thromboxane A₂/prostaglandin H₂ (TP; R >> S) receptors. Our laboratory has reported the effects of

Full text of DOI:10.1021/jm950896w

J . Med. Chem. 1997, 40, 85-91
85
Syn th esis a n d Eva lu a tion of Tr im etoqu in ol Der iva tives: Novel Th r om boxa n e
A2/P r osta gla n d in H2 An ta gon ists w ith Dim in ish ed â-Ad r en er gic Agon ist Activity
J effrey J . Christoff,†,∇ Luke Bradley,† Duane D. Miller,*,§ Longping Lei,‡ Fernando Rodriguez,‡
Paul Fraundorfer,‡ Karl Romstedt,‡ Gamal Shams,‡ and Dennis R. Feller‡
Divisions of Medicinal Chemistry and Pharmacognosy and of Pharmacology, College of Pharmacy, The Ohio State University,
Columbus, Ohio 43210, and Department of Pharmaceutical Sciences, University of Tennessee, Memphis, Tennessee 38163
Received J uly 22, 1996X
Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism
at â-adrenergic (S . R) and antagonism at thromboxane A2/prostaglandin H2 (TP; R . S)
receptors. Our laboratory has reported the effects of N-alkylation and modification of the
trisubstituted benzyl group in these receptor systems. For iodinated derivative 5, maintaining
potency in TP receptor systems (112%) was coupled with maintaining limited potency in
â-adrenergic receptor systems (34% for â1 and 47% for â2). In this study, several diverse TMQ
derivatives were prepared to probe for binding interactions specific to a particular receptor
system. Planar amidine 2, which was designed to explore the importance of TMQ’s chiral center,
showed a dramatic loss of potency (<1%) in each receptor system. Likewise, the homologation
of a previously described N-benzyl derivative (3) to the N-phenylethyl derivative 4 also showed
reduced potency (<3%) in both receptor systems. However, modification of the trimethoxybenzyl
group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) provided a unique lead for TMQ derivatives
with significant potency in TP receptor systems (91%) and reduced potency in â-adrenergic
receptor systems (4% for â1 and 19% for â2).
Ch a r t 1
In tr od u ction
Trimetoquinol (TMQ, 1, Chart 1) is a potent, nonse-
lective, nonclassical â-adrenergic agonist1 and nonpros-
tanoid thromboxane A2/prostaglandin H2 (TP) antago-
nist.2 This compound contains a trimethoxybenzyl
substituent which produces a chiral center that is
unique among â-agonists and nonprostanoid TP antago-
nists. This chiral center shows a strong stereodepen-
dence for binding to â-adrenergic (S . R)3,4 and TP (R
. S)5-8 receptor systems. Our laboratory has reported
the synthesis and biological evaluation of both N-
alkylated9-12 and modified trisubstituted benzyl TMQ
derivatives.13,14 Of these compounds, only monoiodo (5)
and diiodo (6) analogs retained potency against U46619-
induced platelet aggregation. Monoiodo derivative 5,
however, also retained potency for chronotropic re-
sponses (34% for â1) in guinea pig atria14 and bron-
chorelaxant responses (47% for â2) in guinea pig tra-
chea.14 Therefore, the objective of this research was to
design, synthesize, and evaluate unique TMQ deriva-
tives to probe these receptor systems in an effort to
identify novel binding interactions to further separate
receptor selectivity. These compounds will provide
valuable information for the design of future TMQ
derivatives.
Ch a r t 2
Planar amidine derivative (2) was prepared to inves-
tigate the effect of conformationally restricting the
trimethoxybenzyl substituent. The amidine derivative
lacks a chiral center and tautomerizes between a
dihydroisoquinoline and a stilbene system (Chart 2).
The planar amidine derivative was synthesized to
provide insight on the need for a chiral center for
receptor potency and selectivity.
† Division of Medicinal Chemistry.
Several N-alkylated TMQ derivatives were also pre-
pared in an effort to separate receptor activity.9,11
Although many derivatives generally had reduced po-
tency in each system, receptor subtype selectivity in
â-adrenergic (â2 vs â1 selectivity) and TP (R-subtype vs
‡ Division of Pharmacology.
§ University of Tennessee.
∇ Current address: Department of Pharmaceutical Sciences, Chi-
cago College of Pharmacy, Midwestern University, 555 31st St,
Downers Grove, IL 60515.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
S0022-2623(95)00896-X CCC: $14.00 © 1997 American Chemical Society

86 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Christoff et al.
Sch em e 1
Sch em e 2
τ-subtype) receptor systems was observed.10,12 In an
attempt to restore either â-adrenergic or TP receptor
affinity, the N-substituent of N-benzyl TMQ (3) was
elongated to a phenylethyl homolog (4). This modifica-
tion was designed to probe for a potential binding site
unique to one of these receptor systems.
The aforementioned trimethoxybenzyl substituent is
apparently important for receptor affinity and receptor
activation. It is not found in classical â-adrenergic
agonists or nonprostanoid TP antagonists and may be
significant in identifying important portions of the
receptor(s) for enhanced ligand affinity and/or function.
Several TMQ analogs have been prepared,13 but only
two iodinated derivatives (5 and 6) have similar or
enhanced affinity for human â1- and â2-adrenergic and/
or TP receptors.15,16 Additional derivatives (7-9) which
differ significantly in their physical parameters have
been prepared to probe for unique binding interactions
of TMQ analogs with â-adrenergic and/or TP receptors.
Bisbenzyloxy-protected TMQ9 14 was acylated with
phenylacetyl chloride to give amide 15 which was
reduced with borane/tetrahydrofuran complex to form
amine 16. The benzyl ethers were cleaved with hydro-
chloric acid to yield catecholamine 4 (Scheme 2).
The general preparation of compounds 7-9 begins
with the acylation of the free base of phenylethylamine
10 with the appropriate phenylacetic acid 17 or 18 to
form amides 19 and 20 (Scheme 3). Amides 19 and 20
were cyclized, reduced with sodium borohydride, and
converted to their hydrochloride salts to form tetrahy-
droisoquinolines 21 and 22. The p-nitro derivative 22
was reduced in the presence of the benzyloxy ethers by
catalytic hydrogenation with Raney nickel18 to provide
p-amino derivative 23. The benzyloxy ethers were
removed by heating in concentrated hydrochloric acid
in methanol (1:1) to afford catecholamines 7-9.
Biologica l Resu lts a n d Discu ssion
Each of the catecholamine derivatives described above
has been evaluated for â-adrenergic and TP receptor
activities. â-Adrenergic evaluation was performed in
guinea pig atria (â1) and tracheal (â2) strips to evaluate
increased heart rate and smooth muscle relaxant prop-
erties respectively. TP antagonist properties (R-sub-
type)19 were determined from the ability of these
catecholamines to inhibit agonist U46619-induced plate-
let activation (aggregation and serotonin secretion) and
to inhibit [3H]SQ 29,548 binding to TP receptors.
Within each set of experiments, EC50 and IC50 values
Ch em istr y
Phenylethylamine hydrochloride 10 was converted to
its free base, mixed with a toluene solution of isocyan-
ate17 11 at room temperature, and subsequently heated
to reflux to produce urea 12 (Scheme 1). The urea was
cyclized to produce a mixture of compounds which were
separated by silica gel chromatography. (Benzyloxy)-
amidine 13 was isolated as its hydrochloride salt and
converted to catechol 2 with concentrated hydrochloric
acid in methanol (1:1).

Synthesis and Evaluation of TMQ Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 87
Sch em e 3
Ta ble 1. Comparative Adrenergic Agonist Activities of
Trimetoquinol Analogs on Guinea Pig Right Atrial (â1) and
Tracheal (â2) Tissues
Ta ble 2. Comparative Potencies of Trimetoquinol Derivatives
for the Inhibition of U46619-Induced (1 µM) Human Platelet
Activation (Aggregation and Serotonin Secretion) and [H3]SQ
29,548 Binding (5 nM) to TP Receptors
a
pD2
a
pIC50
compd
â1 (n ) 3-9)
â2 (n ) 4-9)
binding [H3]SQ 29,548
platelet
compd aggregation
serotonin
secretion
1
2
4
7
8
9
7.36 ( 0.14
ND
4.62 ( 0.36
5.91 ( 0.31
7.26 ( 0.26
6.21 ( 0.04
7.26 ( 0.08
3.95 ( 0.12
4.64 ( 0.23
6.55 ( 0.15
7.49 ( 0.12
6.75 ( 0.10
a
pIC50
pKib
1
2
4
7
8
9
5.94 ( 0.21
3.70 ( 0.12
4.42 ( 0.12
5.90 ( 0.10
4.35 ( 0.05
3.89 ( 0.04
5.88 ( 0.13 6.35 ( 0.10 6.76 ( 0.09
3.69 ( 0.19 3.56 ( 0.03 3.92 ( 0.07
4.46 ( 0.36 4.38 ( 0.18 4.79 ( 0.18
5.95 ( 0.19 6.06 ( 0.19 6.47 ( 0.19
4.22 ( 0.07 4.60 ( 0.15 5.02 ( 0.15
3.84 ( 0.04 4.05 ( 0.04 4.46 ( 0.04
a
pD2 ) -log EC50. ND ) not determined.
a
b
were standardized to TMQ to minimize the variation
of experimental results over time. For comparison
purposes, the potency and selectivity ratios for new and
previously reported compounds9,14 are listed in Table
3.
pIC50 ) -log IC50
.
pKi ) -log Ki.
derivative 3 in U46619-induced platelet aggregation
studies (Table 3) but provides no significant improve-
ment in the overall biological profile when compared
directly to TMQ (1).
Amidine TMQ 2 is considerably less active than TMQ
in both â-adrenergic and TP receptor systems. This
planar analog is a very weak â2-agonist with a pD2 value
of 3.95 (Table 1). Since this compound was such a weak
â2-agonist, the â1 properties were not evaluated. This
compound also showed very weak TP antagonism with
a pIC50 of 3.70 for U46619-induced platelet aggregation
and 3.69 for U46619-induced serotonin secretion and a
pKi of 3.92 for competitive binding of [3H]SQ 29,548 to
human platelets (Table 2). Thus, the conversion of the
chiral center of TMQ (1) into a planar amidine provides
additional support for the importance of the chiral
center for stereoselective interaction of TMQ with the
appropriate receptor system.
Homologation of N-benzyl TMQ (3) to the N-phenyl-
ethyl derivative 4 further reduced â-adrenergic activity.
The N-phenylethyl homolog was a weak agonist in both
â1 and â2 with pD2 values of 4.62 and 4.64, respectively
(Table 1), and had similar or 10-fold loss of â-adrenergic
activity when compared to N-benzylTMQ (3) (Table 3).
This homolog was also a weak TP antagonist with a
pIC50 of 4.42 for U46619-induced platelet aggregation
and 4.46 for U46619-induced serotonin secretion and a
pKi of 4.79 for competitive binding of [3H]SQ 29,548 to
human platelets (Table 2). N-Phenylethyl TMQ (4) has
similar potency to the previously reported N-benzyl
Several 1-benzyl derivatives 7-9 were evaluated for
their â-adrenergic activity in guinea pig atria and
trachea. Modification of the trimethoxybenzyl substitu-
ent in TMQ (1) to either a mono- or disubstituted benzyl
group provided nitrophenol (7), nitrophenyl (8), and
aniline (9) derivatives with significant â-adrenergic
agonist activity for at least one â-adrenergic receptor
(Table 1). In each case, monosubstitution or disubsti-
tution of the 1-benzyl group provided â2-adrenergic
selectivity greater than that of the prior trisubstituted
derivatives (Table 3). p-Nitrobenzyl derivative 8 was
the most potent compound with a pD2 value of 7.49 for
â2-receptors but was the least selective compound of the
new analogs (Table 3). The rank order of potency of
increased heart rate (â1) in comparison to TMQ (1) is
TMQ (1) g nitrophenyl (8) > aniline (9) g nitrophenol
(7), while the rank order of potency of tracheal smooth
muscle (â2) relaxation is nitrophenyl (8) g TMQ (1) >
aniline (9) g nitrophenol (7).
The comparative potencies of modified benzyl deriva-
tives 7-9 to inhibit U46619-induced platelet activation
and [3H]SQ 29,548 binding to TP receptors is shown in
Table 2. The rank order of potency of TP antagonist
properties for the inhibition of U46619-induced platelet
aggregation and serotonin secretion is nitrophenol (7)

88 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Christoff et al.
Ta ble 3. Comparative Selectivities of Trimetoquinol and Modified Derivatives on Guinea Pig Heart and Trachea and Human
Platelet Aggregation
potency ratioa
selectivity ratiob
aggregation/â1
compd
â1
â2
platelet aggregation
â2/â1
aggregation/â2
1
2
3
4
5
6
7
8
9
1.00
ND
1.00
1.00
1.00
ND
1.00
ND
19.1
16.8
3.31
10.7
1.00
11.9
1.38
12.7
2.40
24.0
4.84 × 10-4
2.40 × 10-2
2.37 × 10-3
0.47
5.75 × 10-3
3.31 × 10-2
3.02 × 10-2
1.12
1.74 × 10-3
1.80 × 10-3
0.34
13.8
1.32
1.38
0.45
5.50
2.14
4.37
7.07 × 10-2
3.50 × 10-2
0.79
3.16 × 10-2
0.76
0.19
0.91
26.0
4.73
1.68
0.31
2.57 × 10-2
3.3 × 10-2
1.53 × 10-2
7.00 × 10-2
8.91 × 10-3
0.13
2.92 × 10-2
a
b
Potency ratio ) EC50(TMQ)/EC50 (drug). Selectivity ratio ) potency ratio(â2 or aggregation)/potency ratio(â1 or â2). ND ) not
determined.
Anhydrous tetrahydrofuran was dried and stored over sodium
with benzophenone as an indicator. Dry toluene was stored
over anhydrous magnesium sulfate and filtered prior to use.
Anhydrous toluene was stored over sodium and distilled prior
to use. Anhydrous acetonitrile was heated to reflux for at least
3 h with phosphorus pentoxide, distilled, and stored over 4A
molecular sieves. Brine was diluted with distilled water to
prepare one-fourth strength and one-half strength brine. All
other reagents were used as received from commercial sup-
pliers. All work was completed under an inert argon atmo-
sphere whenever possible.
N -(2-(3,4-Bis(b e n zyloxy)p h e n yl)e t h yl)-N ′-(3,4,5-t r i-
m et h oxyp h en yl)u r ea (12). 3,4-Bis(benzyloxy)phenethyl-
amine hydrochloride (10) (3.0 g, 8.1 mmol) was converted to
its free base with 5% aqueous NaOH (100 mL) and CH2Cl2
(100 mL). The organic layer was washed with one-fourth
strength brine (100 mL), dried over anhydrous MgSO4, and
evaporated in vacuo. The resulting oil was dissolved in dry
toluene (75 mL). Isocyanate 11 (1.8 g, 8.6 mmol) was dissolved
in dry toluene (25 mL) and added to the amine solution. The
resulting mixture was heated to reflux for 30 min. The
condenser was removed, and the mixture was concentrated to
ca. 50 mL and allowed to cool. The deposited crystals were
collected by vacuum filtration to yield 3.05 g (69%) of a white
solid, mp 160-162 °C. 1H NMR (CDCl3/TMS): δ 7.44-7.28
(m, 10 H, ArH), 6.85 (d, J ) 8.1 Hz, 1H, ArH), 6.80 (d, J ) 2.0
Hz, 1H, ArH), 6.68 (dd, J ) 8.1, 2.0 Hz, 1H, ArH), 6.48 (s, 2H,
ArH), 6.12 (s, 1H, ArNH), 5.11 (s, 4H, 2 x ArCH2O), 4.63 (t, J
) 5.8 Hz, 1H, NHCH2), 3.79 (s, 3H, CH3O), 3.76 (s, 3H, CH3O),
3.47-3.39 (m, 2H, NHCH2), 2.23 (t, J ) 6.7 Hz, 2H, ArCH2).
FAB MS: m/ z 543.3 (MH+). Anal. (C32H34N2O6) C, H, N.
6,7-Bis(ben zyloxy)-1-((3,4,5-tr im eth oxyp h en yl)a m in o)-
3,4-d ih yd r oisoqu in olin e Hyd r och lor id e (13). Urea 12
(500 mg, 0.92 mmol) was dissolved in POCl3 (5 mL) and
anhydrous CH3CN (50 mL) and heated to reflux for 4.5 h. After
cooling to room temperature, solvent was removed in vacuo.
The residue was dissolved in CHCl3 (50 mL), washed with 5%
aqueous NaOH (50 mL) and one-half strength brine (50 mL),
dried over anhydrous MgSO4, and evaporated in vacuo. The
resulting oil was subjected to silica gel chromatography with
CH3OH/benzene/Et3N (5/95/0.5) as the eluent. Appropriate
fractions were pooled and evaporated in vacuo. Anhydrous
HCl(g) was bubbled into a solution of the residue in CHCl3.
The addition of Et2O resulted in precipitation of the product.
The solid was collected and recrystallized from saturated
HCl(g)/CH3OH to yield a white solid, mp 154-155 °C. 1H
NMR (CDCl3/TMS): δ 7.96 (s, 1H, dN+HR), 7.51-7.27 (m,
11H, ArH), 6.74 (s, 1H, ArH), 6.22 (s, 2H, ArH), 5.21 (s, 2H,
ArCH2O), 5.20 (s, 2H, ArCH2O), 5.02 (bs, 1H, ArNHR), 3.84
(s, 9H, 3 × CH3O), 3.37 (t, J ) 6.3 Hz, 2H, N+CH2), 2.85 (t, J
) 6.3 Hz, 2H, ArCH2). FAB MS: m/ z 525.4 (MH+ - HCl).
Anal. (C32H33N2O5Cl1‚1/4H2O) C, H, N.
) TMQ (1) . nitrophenyl (8) > aniline (9), while the
rank order of potency of TP antagonist properties for
the inhibition of [3H]SQ 29,548 binding is TMQ (1) g
nitrophenol (7) > nitrophenyl (8) > aniline (9). The
modification of the 1-benzyl substituent to the nitro-
phenol derivative 7 retained significant potency for TP
antagonism that is comparable to previously synthe-
sized14 monoiodo TMQ derivative 5. The potency of
nitrophenol 7 in a TP receptor system with a concurrent
loss of activity in â-adrenergic receptor systems suggests
that this compound may be a potential new lead
compound for optimization of TP antagonist selectivity.
This compound’s affinity for TP receptors may be due
to an ionic interaction between the phenolic hydroxyl
group and a complementary cationic group on the TP
receptor. The lack of significant potency for aniline 9
reduces the importance of potential hydrogen-bonding
interactions of nitrophenol 7 with this receptor.
In summary, several unique TMQ analogs have been
prepared to study interactions with â-adrenergic and
TP receptor systems. The synthesis and biological
evaluation of amidine TMQ 2 supports the results of
prior studies4,6-8 which demonstrate the importance of
a chiral center for affinity in each receptor system.
Homologation of N-benzyl TMQ 3 to N-phenylethyl
TMQ 4 did not provide additional receptor affinity in
either receptor system. Nitrophenol 7, however, did
provide comparable affinity to TMQ (1) in the TP
receptor system with a concurrent reduction of affinity
in the â-adrenergic system. This disubstituted 1-benzyl
derivative provides our group with a new lead for
optimizing interactions with TP receptors since previ-
ously studied trisubstituted 1-benzyl derivatives dis-
played significant â-adrenergic affinity.
Exp er im en ta l Section
Melting points are uncorrected and were determined with
a Thomas-Hoover melting point apparatus. NMR spectra were
obtained at The Ohio State University College of Pharmacy,
with either an IBM NR-250 FTNMR or an IBM AF-270
FTNMR spectrometer, and are reported in parts per million
relative to tetramethylsilane. Mass spectra were obtained at
The Ohio State University College of Pharmacy with a Kratos
MS25RFA mass spectrometer or at The Ohio State University
Chemical Instrument Center with either a VG 70-250S, Nicolet
FTMS-2000, or Finnigan MAT-900 mass spectrometer. Fast
atom bombardment mass spectroscopy (FAB MS) utilized
3-nitrobenzyl alcohol as solvent unless otherwise noted. In-
frared spectra were obtained at The Ohio State University
College of Pharmacy with an Analect RFX-40 FTIR spectrom-
eter. Elemental analyses were performed by Oneida Research
Services, Inc. (Whitesboro, NY), or by Galbraith Laboratories,
Inc. (Knoxville, TN), within (0.4% of the theoretical values.
6,7-Dih yd r oxy-1-((3,4,5-tr im eth oxyp h en yl)a m in o)-3,4-
d ih yd r oisoqu in olin e Hyd r och lor id e (2). Amidine 13 (500
mg, 0.89 mmol) was dissolved in a mixture of CH3OH (20 mL)
and concentrated HCl (20 mL). The mixture was heated to
reflux for 5 h, cooled to room temperature, and evaporated in
vacuo. The residue was rinsed with IpOH (20 mL) and

Synthesis and Evaluation of TMQ Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 89
evaporated in vacuo. The resulting oil was recrystallized from
CH3OH/Et2O to yield 300 mg (89%) of an off-white solid, dp
169-171 °C (with darkening). 1H NMR (D2O): δ 7.28 (s, 1H,
ArH), 6.76 (s, 1H, ArH), 6.63 (s, 2H, ArH), 3.70 (s, 6H, 2 ×
CH3O), 3.67 (s, 3H, CH3O), 3.33 (t, J ) 6.7 Hz, 2H, N+CH2),
2.74 (t, J ) 6.7 Hz, 2H, ArCH2). FAB MS: m/ z 345.1 (MH+
- HCl). Anal. (C18H21N2O5Cl1‚H2O) C, H, N.
HCl, evaporated in vacuo, rinsed with EtOH (10 mL), filtered,
and evaporated in vacuo. Recrystallization from minimal hot
absolute EtOH/Et2O yielded 55 mg (60%) of a tan solid, dp
122-125 °C (with darkening). 1H NMR (D2O): δ 7.20-7.08
(m, 5H, ArH), 6.64 (s, 1H, ArH), 6.24 (s, 2H, ArH), 5.87 (s,
1H, ArH), 4.40-4.38 (m, 1H, ArCHN), 3.60 (s, 9H, 3 × CH3O),
3.38-3.31 (m, 4H, 2 × CH2), 3.30-2.92 (m, 6H, 3 × CH2). FAB
MS: m/ z 450.2 (MH+ - HCl). Anal. (C27H32N1O5Cl1‚2H2O)
C, H, N.
6,7-Bis(ben zyloxy)-2-(p h en yla cetyl)-1-(3,4,5-tr im eth ox-
yben zyl)-1,2,3,4-tetr a h yd r oisoqu in olin e (15). Amine ox-
alate 14 (500 mg, 0.81 mmol) was converted to its free base
with 10% aqueous NaOH (50 mL) and CH2Cl2 (50 mL). The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (50 mL). The organic extracts were combined,
washed with 10% aqueous NaOH (100 mL) and one-fourth
strength brine (100 mL), and dried over anhydrous MgSO4.
The organic solution was charged with anhydrous MgSO4 (5.0
g) and anhydrous Na2CO3 (5.0 g). The suspension was
vigorously stirred for 15 min before a solution of phenylacetyl
chloride (0.2 mL, 1.51 mmol) in CH2Cl2 (20 mL) was added
dropwise over 5 min at room temperature. The suspension
was stirred for 30 min and filtered. The organic layer was
washed successively with 1.2 N HCl (100 mL), one-fourth
strength brine (100 mL), 5% aqueous NaOH (2 × 100 mL),
and one-fourth strength brine (100 mL) and dried over
anhydrous MgSO4. The solvent was evaporated in vacuo. The
clear white oil was dissolved in a minimal amount of hot
CH3OH. After cooling to room temperature, the flask was
placed in the freezer. The deposited solid was collected after
72 h to yield 374 mg (72%) of a white solid, mp 122-123 °C.
The compound is a mixture of two conformations in solution
N-((3,4-Bis(b en zyloxy)p h en yl)et h yl)(4-h yd r oxy-3-n i-
t r op h en yl)a cet a m id e (19). 3,4-Bis(benzyloxy)phenethy-
lamine hydrochloride (10) (10.0 g, 27.0 mmol) was converted
to its free base with 5% aqueous NaOH (100 mL) and CH2Cl2
(100 mL). The layers were separated, and the organic layer
was washed with brine (100 mL), dried over anhydrous MgSO4,
and evaporated in vacuo. The light brown oil was dissolved
in toluene (125 mL) and charged with 4-hydroxy-3-nitrophen-
ylacetic acid 17 (5.86 g, 29.7 mmol). The suspension was
heated to reflux for 72 h with azeotropic removal of water by
a Dean-Stark trap. After cooling to room temperature,
solvent was removed in vacuo. The residue was dissolved in
dichloromethane (100 mL), washed with a solution of NH4-
HCO3 (5 g/100 mL), saturated NH4Cl (100 mL), and brine (100
mL), dried over anhydrous MgSO4, and evaporated in vacuo.
The product was recrystallized in two crops from a minimal
amount of hot toluene to yield 9.3 g (67%) of a bright yellow
solid, mp 135-137 °C. 1H NMR (CDCl3): δ 10.51 (bs, 1H, OH),
7.91 (d, J ) 2.2 Hz, 1H, ArH ortho to NO2), 7.48-7.29 (m, 11H,
10 × ArH, ArH para to NO2), 7.08 (d, J ) 8.7 Hz, 1H, ArH
meta to NO2), 6.82 (d, J ) 8.2 Hz, 1H, ArH), 6.71 (d, J ) 2.0
Hz, 1H, ArH), 6.58 (dd, J ) 8.2, 2.0 Hz, 1H, ArH), 5.33 (bt,
1H, NH), 5.13 (s, 2H, ArCH2O), 5.12 (s, 2H, ArCH2O), 3.47-
3.39 (m, 2H, NCH2), 3.39 (s, 2H, ArCH2CO), 2.67 (t, J ) 6.7
Hz, 2H, ArCH2). FAB MS: m/ z 513.4 (MH+). Anal.
(C30H28N2O6) C, H, N.
1
providing a complex H NMR spectrum. Temperature eleva-
tion studies in CDCl3 to 323 K and DMSO-d6 to 357 K did not
simplify the 1H NMR spectrum in order to assign proton
resonances. FAB MS: m/ z 644.3 (MH+). Anal. (C41H41N1O6)
C, H, N.
6,7-Bis(ben zyloxy)-2-(2-ph en yleth yl)-1-(3,4,5-tr im eth ox-
yben zyl)-1,2,3,4-tetr ah ydr oisoqu in olin e Oxalate Salt (16).
A solution of BH3/THF complex (5.0 mL, 5.0 mmol) was added
to a solution of amide 15 (900 mg, 1.40 mmol) in anhydrous
THF (25 mL). The resulting solution was heated to reflux for
2.5 h and subsequently cooled to room temperature. Excess
reagent was quenched by the addition of EtOH (5 mL), and
solvent was evaporated in vacuo. The residue was dissolved
in CH2Cl2 (50 mL) and 5% aqueous NaOH (100 mL). The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (50 mL). The organic extracts were combined,
successively washed with 5% aqueous NaOH (100 mL), and
one-fourth strength brine (2 × 100 mL), dried over anhydrous
MgSO4, and evaporated in vacuo. The resulting oil was
dissolved in Et2O (25 mL) and added dropwise to a solution of
oxalic acid dihydrate (197 mg, 1.40 mmol) in Et2O (25 mL).
After standing overnight, the precipitate was collected to yield
845 mg (84%) of a white solid, mp 214-216 °C. 1H NMR (free
base, CDCl3/TMS): δ 7.42-7.15 (m, 15H, ArH), 6.66 (s, 1H,
ArH), 6.29 (s, 2H, ArH), 6.19 (s, 1H, ArH), 5.10 (s, 2H,
ArCH2O), 4.87 (ABq, J ) 13.7 Hz, ∆υ ) 20.5 Hz, 2H, ArCH2O),
3.82 (s, 3H, CH3O), 3.77 (s, 6H, 2 × CH3O), 3.25-3.15 (m, 1H,
ArCHN), 3.09-2.66 (m, 8H, 4 × CH2), 2.52-2.43 (m, 2H, CH2).
FAB MS: m/ z 630.3 (MH+ - C2H2O4). Anal. (C43H45N1O9)
C, H, N.
6,7-Dih yd r oxy-2-(2-p h en ylet h yl)-1-(3,4,5-t r im et h oxy-
ben zyl)-1,2,3,4-tetr ah ydr oisoqu in olin e Hydr och lor ide (4).
Amine 16 (200 mg, 0.28 mmol) was converted to its free base
with 5% aqueous NaOH (50 mL) and CH2Cl2 (50 mL). The
layers were separated, and the organic layer was washed with
one-fourth strength brine (50 mL), dried over anhydrous
MgSO4, and evaporated in vacuo. The residue was dissolved
in a mixture of CH3OH (10 mL) and concentrated HCl (10 mL)
and subsequently heated to reflux for 24 h. After cooling to
room temperature, solvent was evaporated in vacuo. The
resulting oil was rinsed three times with EtOH (10 mL) and
evaporated in vacuo. The resulting oil was recrystallized from
EtOH/Et2O to yield 91 mg (67%) of a light brown solid, dp 118-
120 °C (with darkening), which was subjected to silica gel
chromatography with CH3OH/Et2O/NH4OH/CHCl3 (10/10/1/79)
as the eluent. The pooled fractions were acidified with 1.2 N
6,7-Bis(ben zyloxy)-1-(4-h yd r oxy-3-n itr oben zyl)-1,2,3,4-
tetr a h yd r oisoqu in olin e Hyd r och lor id e (21). Amide 19
(3.3 g, 6.4 mmol) was suspended in anhydrous CH3CN (30 mL),
charged with POCl3 (15 mL), and heated to reflux for 3.5 h.
After cooling to room temperature, solvent was removed in
vacuo. The residue was rinsed with anhydrous CH3CN (30
mL) and evaporated in vacuo. The dark green oil was
suspended in EtOH (40 mL) and cooled to 0 °C. NaBH4 (1.21
g, 32 mmol) was added portionwise to avoid excessive foaming.
The suspension was stirred overnight with warming to room
temperature. Solvent was evaporated in vacuo, and the
residue was dissolved in a mixture of EtOAc (100 mL) and
5% NH4OH (100 mL). The layers were separated, and the
organic layer was washed with brine (100 mL), dried over
anhydrous Na2SO4, and evaporated in vacuo. The residue was
dissolved in CH3OH (30 mL) and charged with 3 N HCl/
CH3OH. After stirring at room temperature overnight, the
solid was collected by vacuum filtration to yield 2.21 g (64%)
of an off-white solid, mp 204-207 °C. 1H NMR (CD3OD/
acetone): δ 8.03 (d, J ) 2.0 Hz, 1H, ArH ortho to NO2), 7.57
(dd, J ) 8.6, 2.0 Hz, 1H, ArH para to NO2), 7.44-7.24 (m, 10H,
ArH), 7.14 (d, J ) 8.6 Hz, ArH meta to NO2), 6.93 (s, 1H, ArH),
6.79 (s, 1H, ArH), 5.11 (s, 2H, ArCH2O), 4.97 (s, 2H, ArCH2O),
4.96 (t, J ) 6.0 Hz, 1H, ArCHRN), 3.62-3.34 (m, 4H, CH2),
3.08-3.03 (m, 2H, CH2). EI MS: m/ z 496.3205 (M+). Anal.
(C30H29N2O5Cl1‚1/2H2O) C, H, N.
6,7-Dih yd r oxy-1-(4-h yd r oxy-3-n itr oben zyl)-1,2,3,4-tet-
r a h yd r oisoqu in olin e Hyd r och lor id e (7). Isoquinoline 21
(200 mg, 0.37 mmol) was dissolved in a mixture of concentrated
HCl (4 mL) and CH3OH (4 mL) and heated to reflux overnight.
After cooling to room temperature, solvent was evaporated in
vacuo. The residue was rinsed twice with CH3OH (10 mL)
and evaporated in vacuo. The resulting solid was dissolved
in excess EtOH, filtered, and concentrated by evaporation on
a hot plate to about 5 mL. Et2O was added until the mixture
became cloudy. The deposited solid was collected by vacuum
filtration, rinsed with Et2O, and dried under vacuum at 56 °C
for 36 h to yield 106 mg (82%) of a rust-colored solid, dp 253-
255 °C (with bubbling). 1H NMR (CD3OD): δ 8.05 (d, J ) 2.1
Hz, 1H, ArH ortho to NO2), 7.56 (dd, J ) 8.6 and 2.1 Hz, 1H,
ArH para to NO2), 7.18 (d, J ) 8.6 Hz, 1H, ArH meta to NO2),

90 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Christoff et al.
6.63 (s, 1H, ArH), 6.54 (s, 1H, ArH), 4.66 (t, J ) 7.2 Hz, 1H,
ArCHRN), 3.51-3.41 (m, 2H, CH2), 3.31-3.23 (m, 1H, CH2),
3.14-3.05 (m, 1H, CH2), 3.01-2.92 (m, 2H, CH2). FAB MS:
m/ z 317.1 (MH+ - HCl). Anal. (C16H17N2O5Cl1) C, H, N.
N-((3,4-Bis(b en zyloxy)p h en yl)et h yl)(4-n it r op h en yl)-
a ceta m id e (20). 3,4-Bis(benzyloxy)phenethylamine hydro-
chloride (10) (10.0 g, 27.0 mmol) was converted to its free base
with 5% aqueous NaOH (250 mL) and CH2Cl2 (250 mL). The
layers were separated, and the organic layer was washed with
brine (250 mL), dried over anhydrous MgSO4, and evaporated
in vacuo. The light brown oil was dissolved in toluene (150
mL) and charged with 4-nitrophenylacetic acid (18) (7.2 g, 39.8
mmol). The suspension was heated to reflux for 72 h with
azeotropic removal of water by a Dean-Stark trap. After
cooling to room temperature, solvent was removed in vacuo.
The residue was dissolved in CH2Cl2 (250 mL), washed with
saturated NaHCO3 (2 × 125 mL) and brine (100 mL), dried
over anhydrous MgSO4, and evaporated in vacuo. The product
was recrystallized in two crops from a minimal amount of hot
toluene to yield 10.06 g (75%) of a pale yellow solid, mp 132-
133.5 °C. 1H NMR (CDCl3): δ 8.13 (AA′XX′, J ) 6.8, 2.0 Hz,
ArH ortho to NO2), 7.48-7.27 (m, 12H, ArH, meta to NO2),
6.80 (d, J ) 8.1 Hz, 1H, ArH), 6.72 (d, J ) 2.0 Hz, 1H, ArH),
6.53 (dd, J ) 8.1, 2.0 Hz, 1H, ArH), 5.32 (bt, 1H, NH), 5.14 (s,
2H, ArCH2O), 5.12 (s, 2H, ArCH2O), 3.51 (s, 2H, ArCH2CO),
3.44 (m, 2H, NHCH2), 2.66 (t, 2H, ArCH2CH2). EI MS: m/ z
496 (M+). Anal. (C30H28N2O5) C, H, N.
6,7-Bis(b en zyloxy)-1-(4-n it r ob en zyl)-1,2,3,4-t et r a h y-
d r oisoqu in olin e Hyd r och lor id e (22). To a suspension of
amide 20 (5.0 g, 10.0 mmol) in anhydrous CH3CN (20 mL) at
room temperature was added POCl3 (5 mL), and the resulting
solution was heated to reflux for 4.5 h. The solution was cooled
to room temperature, and solvent was removed in vacuo. The
oily residue was dissolved in CHCl3 (75 mL) and diluted with
an ice slurry (40 mL). The biphasic solution was vigorously
stirred while a 5% solution of NaOH was added dropwise until
the aqueous layer was basic to pH paper. The layers were
separated, and the organic layer was washed with 5% aqueous
NaOH (50 mL) and brine (30 mL), dried over anhydrous
MgSO4, and evaporated in vacuo. The residue was suspended
in EtOH (50 mL) and cooled to 0 °C. NaBH4 (0.95 g, 25 mmol)
was added portionwise with vigorous stirring over 10 min to
prevent excessive foaming. The mixture was allowed to warm
to room temperature with stirring overnight. Solvent was
removed in vacuo, and the residue was partitioned between
EtOAc (100 mL) and water (100 mL). The organic layer was
washed with brine (50 mL), dried over anhydrous MgSO4, and
evaporated in vacuo. The residue was dissolved in CH3OH
(30 mL) and stirred overnight with a solution of saturated
HCl(g)/CH3OH (10 mL). Solvent was removed in vacuo. The
residue was dissolved in hot EtOH, filtered, and concentrated
by evaporation on a hot plate. After cooling, the deposited
product was collected by vacuum filtration and washed with
Et2O to yield 2.37 g (46%) of a light yellow solid, mp 213-
214.5 °C. The mother liquor was evaporated and a second crop
of crystals was produced from hot EtOH to yield an additional
1.36 g (total yield 72%) of a pale yellow solid, mp 210-213 °C.
1H NMR (CD3OD): δ 8.23 (d, J ) 8.7 Hz, 2H, ArH ortho to
NO2), 7.52 (d, J ) 8.7 Hz, 2H, ArH meta to NO2), 7.46-7.26
(m, 10H, ArH), 6.91 (s, 1H, ArH), 6.61 (s, 1H, ArH), 5.14 (s,
2H, ArCH2O), 4.95 (s, 2H, ArCH2O), 4.80 (t, J ) 7.2 Hz, 1H,
ArCHRN), 3.58-3.49 (m, 2H, 4-NO2ArCH2), 3.39-3.22 (m, 2H,
NCH2), 3.06-2.98 (m, 2H, ArCH2CH2). FAB MS: m/ z 481.4
(MH+ - HCl). Anal. (C30H29N2O4Cl1‚H2O) C, H, N.
CH2N), 3.02-2.94 (m, 2H, ArCH2). FAB MS: m/ z 301.2 (MH+
- HCl). Anal. (C16H17N2O4Cl1‚1/2H2O) C, H, N.
1-(4-Am in ob en zyl)-6,7-bis(b en zyloxy)-1,2,3,4-t et r a h y-
d r oisoqu in olin e Dih yd r och lor id e (23). p-Nitrobenzyl de-
rivative 22 (500 mg, 0.97 mmol) was dissolved in CH3OH (20
mL) in a Parr bottle. The solution was charged with a slurry
of Raney nickel (0.25 mL) and hydrogenated at 50 psi for 2 h.
The mixture was double filtered and evaporated in vacuo. The
oily residue was dissolved in CH3OH (5 mL) and charged with
a solution of 3 N HCl/CH3OH (1 mL). After stirring for 4 h,
solvent was evaporated in vacuo. The solid residue was
dissolved in minimal hot CH3OH and diluted with Et2O until
the mixture became cloudy. The solid was collected by vacuum
filtration to yield 408 mg (81%) of an off-white solid, mp 211-
213 °C. 1H NMR (CD3OD): δ 7.48-7.25 (m, 14H, ArH), 6.91
(s, 1H, ArH), 6.65 (s, 1H, ArH), 5.13 (s, 2H, ArCH2O), 4.97 (s,
2H, ArCH2O), 4.75 (t, J ) 7.5 Hz, 1H, ArCHRN), 3.54-3.16
(m, 4H, 2 × CH2), 3.06-2.98 (m, 2H, CH2). FAB MS: m/ z
451.4 (MH+ - 2HCl). Anal. (C30H32N2O2Cl2‚1/4H2O) C, H, N.
1-(4-Am in oben zyl)-6,7-dih ydr oxy-1,2,3,4-tetr ah ydr oiso-
qu in olin e Dih yd r och lor id e (9). Amine 23 (200 mg, 0.38
mmol) was dissolved in a mixture of concentrated HCl (4 mL)
and CH3OH (4 mL) and heated to reflux overnight. After
cooling to room temperature, solvent was evaporated in vacuo.
The residue was rinsed twice with CH3OH (10 mL) and
evaporated in vacuo. The resulting solid was recrystallized
from EtOH/Et2O. The deposited solid was collected by vacuum
filtration, rinsed with Et2O, and dried under vacuum for 36 h
at 56 °C to yield 88 mg (66%) of a tan solid, mp 260-262 °C.
1H NMR (CD3OD): δ 7.52-7.40 (AA′BB′, 4H, ArH ortho and
meta to NH2) 6.63 (s, 1H, ArH), 6.47 (s, 1H, ArH), 4.70 (t, J )
7.3 Hz, 1H, ArCHRN), 3.53-3.43 (m, 2H, CH2), 3.33-3.28 (m,
1H, CH2), 3.26-3.17 (m, 1H, CH2), 3.02-2.93 (m, 2H, CH2).
FAB MS: m/ z 271.1 (MH+ - 2HCl). Anal. (C16H20N2O2Cl2‚1/
2H2O) C, H, N.
â-Ad r en er gic Recep tor Stu d ies. Male albino Hartley
guinea pigs weighing 300-400 g were used. Isolation of
tissues and preparation of spontaneously beating right atria
and carbachol (0.3 µM)-contracted tracheal strips were done
as described previously.10,12 Cumulative concentration-
response curves to each drug were determined. Each succes-
sive drug addition was added only after the effects of the
previous concentration had reached a maximal response, and
the results are expressed relative to the maximal response to
10-5 M isoproterenol added after the completion of each
concentration-response curve.
P la telet In h ibition Stu d ies. Blood was collected from
normal human volunteers who reported to be free of medica-
tion for at least 10 days. Platelet-rich plasma (PRP) was
prepared and used for studies for inhibition of aggregation and
serotonin secretion by drugs in the presence of U46619, a TP
agonist as described previously in our laboratory.10,11 Platelet
aggregation experiments were performed according to a tur-
bidometric method in dual-channel aggregometers interfaced
to computers for the acquisition, quantification, presentation,
and management of aggregation data.20 [14C]Serotonin (0.03
µCi/mL) was added to PRP for 20 min prior to the start of the
experiment to allow for uptake of label into dense granules.
U46619 was used at the minimum concentration required to
stimulate maximal aggregation. Aspirin (1 mM) was added
to PRP to block the formation of endogenous prostaglandins.
After a 1 min incubation of PRP samples with aspirin and
drug, U46619 (0.3-1 µM) was added and the aggregation
response monitored for 4 min. Samples were centrifuged, and
a 0.1 mL aliquot of the supernatant was mixed into an
emulsion-type scintillation cocktail for liquid scintillation
spectrometry. Background counting rates (BKG cpm) were
determined from the supernatants of unstimulated samples
and was less than 10% of that released into the supernatants
by U46619 alone. The percent secretion of serotonin was
calculated by the following formula: percent serotonin secre-
tion ) [(sample cpm - BKG cpm)/(total cpm - BKG cpm)] ×
100%, where cpm ) counts per min and total cpm ) amount
of radioactivity in an uncentrifuged sample.
6,7-Dih yd r oxy-1-(4-n itr oben zyl)-1,2,3,4-tetr a h yd r oiso-
qu in olin e Hyd r och lor id e (8). Amine 22 (500 mg, 0.97
mmol) was dissolved in a mixture of concentrated HCl (4 mL)
and CH3OH (4 mL) and heated to reflux overnight. After
cooling to room temperature, solvent was evaporated in vacuo.
The residue was rinsed twice with CH3OH (10 mL) and
evaporated in vacuo. The resulting solid was recrystallized
from EtOH/Et2O to yield 264 mg (81%) of a golden solid, mp
178-179 °C. 1H NMR (CD3OD) : δ 8.26 (d, J ) 8.7 Hz, 2H,
ArH ortho to NO2), 7.56 (d, J ) 8.7 Hz, 2H, ArH meta to NO2),
6.64 (s, 1H, ArH), 6.44 (s, 1H, ArH), 4.74 (t, J ) 7.4 Hz, 1H,
ArCHRN), 3.60-3.47 (m, 2H, NO2ArCH2), 3.34-3.21 (m, 2H,
Ra d ioliga n d Bin d in g Stu d ies w ith Th r om boxa n e A2/
P r osta gla n d in H2 Recep tor Sites in Hu m a n P la telets. For

Synthesis and Evaluation of TMQ Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 91
(8) Ahn, C.; Wallace, L. J .; Miller, D. D.; Feller, D. R. Use of [3H]-
Trimetoquinol as a Radioligand in Human Platelets. Interaction
with Putative Endoperoxide/Thromboxane A2 Receptor Sites.
Thromb. Res. 1988, 50, 387-399.
(9) Adejare, A.; Miller, D. D.; Fedyna, J . S.; Ahn, C.; Feller, D. R.
Syntheses and â-Adrenergic Agonist and Antiaggregatory Prop-
erties of N-Substituted Trimetoquinol Analogues. J . Med. Chem.
1986, 29 (9), 1603-1609.
(10) Fedyna, J . S.; Adejare, A.; Miller, D. D.; Feller, D. R. Pharma-
cological Evaluation of the â-Adrenoceptor Agonist and Throm-
boxane Antagonist Properties of N-Substituted Trimetoquinol
Analogues. Eur. J . Pharmacol. 1987, 135, 161-171.
(11) Harrold, M. W.; Grazyl, B.; Shin, Y.; Romstedt, K. J .; Feller, D.
R.; Miller, D. D. Synthesis and Thromboxane A2 Antagonist
Activity of N-Benzyltrimetoquinol Analogues. J . Med. Chem.
1988, 31 (8), 1506-1512.
binding experiments, human PRP was centrifuged and plate-
lets were resuspended in 50 mM Tris saline buffer, pH 7.2.16
Platelets (1 × 108) were incubated with 5 nM [3H]SQ 29,548
in a final volume of 0.5 mL as modified from Hedberg et al.21
Unlabeled SQ 29,548 (50 µM) was used to determine nonspe-
cific binding. Varying concentrations of each drug were used
to quantify the inhibition of specific [3H]SQ 29,548 binding.
Samples were incubated for 30 min at room temperature, and
rapidly filtered by vacuum through Whatman GF/B glass fiber
filters on a Brandel cell harvester, and washed for 10 s with
ice cold Tris saline buffer. Filters were placed in plastic
scintillation vials containing 10 mL of an emulsion-type
scintillation mixture, and radioactivity was measured by liquid
scintillation spectrometry. Specific binding to human platelets
varied between 88% and 95%.
(12) Shams, G.; Harrold, M. W.; Grazyl, B.; Miller, D. D.; Feller, D.
R. Pharmacological Evaluation of the â-Adrenoceptor Agonist
Properties of N-Benzyl Substituted Trimetoquinol Analogues.
Eur. J . Pharmacol. 1990, 184, 251-256.
(13) Harrold, M. W.; Gerhardt, M. A.; Romstedt, K. J .; Feller, D. R.,
Miller, D. D. Synthesis and Platelet Antiaggregatory Activity
of Trimetoquinol Analogs as Endoperoxide/Thromboxane A2
Antagonists. Drug Des. Delivery 1987, 1, 193-207.
(14) Shams, G.; Romstedt, K. J .; Gerhardt, M. A.; Harrold, M. W.;
Miller, D. D.; Feller, D. R. Pharmacological Evaluation of the
â-Adrenoceptor Agonist and Thromboxane Receptor Blocking
Properties of 1-Benzyl Substituted Trimetoquinol Analogues.
Eur. J . Pharmacol. 1990, 184, 21-31.
Da ta An a lysis. Effective concentration-50 (EC50) and
inhibitory concentration-50 (IC50) values of each drug were
determined graphically from individual plots of percent re-
sponse versus log drug concentration on â-adrenoceptors
(guinea pig atria and trachea) and human platelets, respec-
tively. Individual drug responses were expressed as pD2 (-log
EC50) and pIC50 (-log IC50) values. Dissociation constants (Ki)
for competing drugs in the displacement of specific SQ 29,548
binding were calculated using the equation: Ki ) IC50/(1 +
[L]/KL), where [L] ) the radioligand concentration (5 nM), KL
) the affinity constant of the radioligand (3.1 nM), and pKi )
-log Ki values.16
(15) Fraundorfer, P.; Fertel, R. H.; Miller, D. D.; Feller, D. R.
Biochemical and Pharmacological Characterization of high Af-
finity Trimetoquinol Analogs on Guinea Pig and Human Beta-
adrenergic Subtypes: Evidence for Partial Agonism. J . Phar-
macol. Exp. Ther. 1994, 270, 665-674.
(16) Sin, Y.; Romstedt, K. J .; Miller, D. D.; Feller, D. R. Interactions
of Nonprostanoid Trimetoquinol Analogs with Thromboxane A2/
Prostaglandin H2 Receptors in Human Platelets, Rat Vasular
Endothelial Cells, and Rat Vascular Smooth Muscle Cells. J .
Pharmacol. Exp. Therp. 1993, 267, 1017-1023.
(17) Stogryn, E. L. Synthesis of Trimethoprim Variations. Replace-
ment of CH2 by polar groupings. J . Med. Chem. 1972, 15 (2),
200-201.
(18) White, R. L., J r.; Schwan, T. J .; Alaimo, R. J . Rearrangement of
a Pyranone to a Benzothiazole. J . Heterocycl. Chem. 1980, 17,
817-818.
(19) Mais, D. E.; Saussey, D. L., J r.; Chaikhouni, A.; Kochel, P. J .;
Knapp, D. R.; Hamanaka, N.; Halushka, P. V. Pharmacological
Characterization of Human and Canine Thromboxane A2/Pros-
taglandin H2 Receptors in Platelets and Blood Vessels: Evidence
for Different Receptors. J . Pharmacol. Exp. Ther. 1985, 233,
418-424.
(20) Huzoor-Akbar; Romstedt, K.; Manhire, B. Computerized Ag-
gregation Instrument: A Highly Efficient and Versatile System
for Acquisition, Quantitation, Presentation and Management for
Platelet Aggregation Data. Thromb. Res. 1983, 32, 335-341.
(21) Hedberg, A.; Hall, S.; Ogletree, M. L.; Harris, D. N.; Liu, E. C.
K., Characterization of [5,6-3H]SQ 29548 as a high affinity
radioligand binding to thromboxane A2/prostaglandin H2 recep-
tors in human platelets. J . Pharmacol. Exp. Ther. 1988, 245,
786-792.
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (NIH HL22533), the Ameri-
can Foundation for Pharmaceutical Education, and both
the College of Pharmacy and the Graduate School at
The Ohio State University is appreciated.
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